Artemin alters the functional properties of jugular C-fibers

Neurotrophic factors have been shown to alter the functional properties of sensory C-fibers in allergic asthma. Artemin is a neurotrophic factor in the Glial Cell Line-Derived Neurotrophic Factor (GDNF) family of ligands, binds to its receptor GFRα3 and initiates intracellular signaling via co-receptor RET. Previously, we were able to demonstrate that a subpopulation of bronchopulmonary vagal C-fibers, namely the jugular cells, co-express GFRα3 and RET (Nassenstein et al., J Physiol 2010). These cells also showed expression of the transient receptor potential channel vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1). Dysfunction of the TRPV1 and TRPA1 receptors (which bind many environmental irritants and endogenous inflammatory mediators) has been associated with an enhanced sensory C-fiber excitability. The aim of the study was, therefore, to investigate if artemin is expressed in the airways and to define the role of artemin on TRPV1 and TRPA1 sensitivity in jugular C-fibers. After we were able to demonstrate that artemin was expressed in murine lungs, dissociated vagal sensory neurons were treated with recombinant artemin (50ng/ml) for 4h and 24h and intracellular calcium was analyzed in neural-crest C-fibers in response to increasing doses of cinnamaldehyde (TRPA1 ligand) and capsaicin (TRPV1 ligand). Interestingly, artemin caused a phenotypic switch in jugular C-fibers by increasing the number of TRPA1 responsive cells. Furthermore, artemin increased the capsaicin-induced intracellular calcium influx in jugular C-fibers Taken together, these results indicate that artemin modulates functional properties of neural crest C-fiber neurons.